Many inflammatory disease not only have a female preponderance, but are also associated with greater severity of pain and inflammation in females. While the mechanisms underlying sex differences in inflammatory pain are still not well understood, considerable literature suggests that sex steroids play an important role in sex differences in both pain and response to analgesics, and in the inflammatory process. Although previous literature indicates that sex steroids mediate sex differences in central nociceptive mechanisms, little is known about their effects on peripheral nociceptive and anti- nociceptive mechanisms. Sex steroid receptors are present on sensory neurons and the investigators' preliminary experiments show that both female and male sex steroids appear to affect the primary afferent nociceptor to modulate its response to hyperalgesic inflammatory mediators. The investigator propose to extend these finds and to elucidate the underlying mechanisms by which sex differences in hyperalgesia and anti-nociception occur. Sex steroids have also been implicated in the sex differences seen in the inflammatory mediators that produce pain in patients with inflammatory diseases. The investigators propose to test the hypotheses that: 1) sex differences in inflammation are due to differences in the sex steroids in female and male rats; 2) the effect(s) of sex steroids may differentially regulate components of the inflammatory response (blood flow, plasma extravasation, and neutrophil accumulation); and 3) the effects of sex steroids on inflammation are mediated by activity of the hypothalamo-pituitary-adrenal axis. In summary, the investigators propose to test the hypothesis that sex steroids affect inflammatory pain both by modulating the severity of the inflammatory response, and hence, the production of hyperalgesic inflammatory mediators as well as the response of primary afferent nociceptors to these mediators. Using gonadal ablation and sex steroid replacement experiments, they will evaluate the mechanisms by which female and male sex steroids contribute to the differences in peripheral nociception and anti- nociception, and the components of the inflammatory response.
